Spanish Consensus Statement on alternatives to allogeneic blood transfusion: the 2013 update of the "Seville Document"

Transcription

1 R Spanish Consensus Statement on alternatives to allogeneic blood transfusion: the 2013 update of the "Seville Document" Santiago R. Leal-Noval 1, Manuel Muñoz 2, Marisol Asuero 3, Enric Contreras 3, José A. García-Erce 3, Juan V. Llau 3, Victoria Moral 3, José A. Páramo 3, Manuel Quintana 3, for the Spanish Expert Panel on Alternatives to Allogeneic Blood Transfusion 4 1 General coordinator, 2 General Vice-coordinator, 3 Topic coordinator (in alphabetical order); 4 see Appendix A. Paper commissioned and endorsed by (in alphabetical order) Spanish Societies of Anaesthesiology and Reanimation (SEDAR), Critical Care Medicine (SEMICYUC), Haematology and Haemotherapy (SEHH), Hospital Pharmacy (SEFH), Thrombosis and Haemostasis (SETH), and Transfusion and Cellular Therapy (SETS) Summary of recommendations on alternatives to reduce allogeneic blood transfusion (in descending order of strength) Grade 1A recommendations We recommend: - The use of restrictive transfusion strategies in nonbleeding, euvolaemic anaemic patients. - Perioperative administration of tranexamic acid to patients undergoing cardiac surgery. - The administration of intravenous iron to cancer patients, as an adjuvant to erythropoiesis-stimulating agents, for correcting chemotherapy-induced anaemia. - Preoperative administration of erythropoiesisstimulating agents to anaemic, orthopaedic surgical patients expected to have moderate blood losses. We do not recommend: - The administration of desmopressin to patients undergoing elective surgery. - The administration of erythropoiesis-stimulating agents to critically ill patients who do not have a previous indication for this therapy. Grade 1B recommendations We recommend: - Perioperative cell salvage in patients undergoing surgery for total hip or knee arthroplasty, cardiac procedures with cardiopulmonary bypass, or abdominal aorta aneurysm repair. - Perioperative administration of epsilon-aminocaproic acid to patients undergoing cardiac surgery. - Perioperative administration of tranexamic acid to patients undergoing hepatic surgery or bleeding trauma. - The administration of intravenous iron to patients with post-partum anaemia or inflammatory bowel disease associated anaemia. We do not recommend: - Preoperative autologous blood donation in surgical procedures generally requiring the transfusion of two or fewer units of packed red cells. - Routine use of acute normovolaemic haemodilution, as the single blood-sparing technique, in major surgery. - Perioperative administration of epsilon-aminocaproic acid in orthopaedic surgical procedures. - The administration of oral iron in the postoperative period or in critically ill patients. Grade 1C recommendations We recommend: - Preoperative autologous blood donation in orthopaedic surgical procedures generally requiring the transfusion of three or more units of packed red cells. - Perioperative cell salvage in complex spinal surgery, in combination with other blood-saving strategies. - The use of thromboelastography in surgical or trauma patients presenting with severe bleeding. - The administration of prothrombin complex concentrates to patients treated with vitamin K antagonists and presenting with intracranial haemorrhage. - Thromboelastography-guided administration of fibrinogen concentrates to surgical or trauma patients presenting with severe bleeding. - Fluid resuscitation in patients with mild to moderate blood losses. Grade 2A recommendations We suggest: - The administration of prothrombin complex concentrates to patients treated with vitamin K antagonists and presenting with active bleeding or undergoing urgent or emergent surgery. - Perioperative administration of tranexamic acid to patients undergoing lower limb arthroplasty, This document is simultaneously published in the following Journals: Medicina Intensiva, Revista Española de Anestesiología y Reanimación, Farmacia Hospitalaria ("2013. Documento Sevilla de Consenso sobre Alternativas a la Transfusión de Sangre Alogénica. Actualización del Documento Sevilla"), and Blood Transfusion ("Spanish Consensus Statement on alternatives to allogeneic blood transfusion: the 2013 update of the «Seville Document»"). 585

2 Leal-Noval SR et al extensive spinal instrumentation, gynaecological cancer surgery, or radical prostatectomy. - The administration of tranexamic acid to patients presenting with gastrointestinal bleeding due to ulcer or mucosal erosion. - Perioperative administration of erythropoiesisstimulating agents to patients undergoing cardiac or gastrointestinal cancer surgery. Grade 2B recommendations We suggest: - Preoperative autologous blood donation in patients undergoing surgery for colorectal, prostatic or hepatic cancer resection, generally with adjuvant treatment with erythropoiesis-stimulating agents, as well as in cardiac procedures with cardiopulmonary bypass. - Thromboelastography-guided fibrinogen concentrates to patients undergoing cardiac, aortic aneurysm repair, or radical cystectomy surgical procedures, as well as in obstetric haemorrhage. - Preoperative oral iron administration in patients undergoing orthopaedic or colorectal cancer surgery. - Perioperative intravenous iron administration to anaemic patients scheduled for orthopaedic, gynaecological or gastrointestinal surgery. - The administration of intravenous iron, without erythropoiesis-stimulating agents, for treating radiotherapy- or chemotherapy-induced anaemia in cancer patients. - Fluid resuscitation in patients with severe blood losses. Grade 2C recommendations We suggest: - Perioperative cell salvage in patients undergoing hepatic or urological cancer surgery, abdominal trauma, Caesarean section, or ruptured ectopic pregnancy. - Thromboelastography-guided administration of prothrombin complex concentrates to patients not on vitamin K antagonists and presenting with bleeding trauma, perioperative haemorrhage or acute liver failure. - The administration of prothrombin complex concentrates, instead of fresh-frozen plasma, to patients on vitamin K antagonists who need immediate reversal of anticoagulation. - The administration of recombinant activated factor VII to patients presenting with severe or refractory haemorrhage, including intracranial haemorrhage and postoperative haemorrhage after cardiac or liver surgery. - Postoperative intravenous iron administration for treating postoperative anaemia after cardiac, obstetrics and gynaecological or orthopaedic surgical procedures. Grade 0 recommendation We cannot make any evidence-based recommendation on the use of perfluorocarbon- and haemoglobin-based oxygen carriers as alternatives to allogeneic blood transfusion. 1. Background and objectives The Spanish Consensus Statement on Alternatives to Allogeneic Blood Transfusion (AABT), so-called the Seville Document (SD), was first published in The original purpose of the SD was to generate recommendations based on the best available evidence on AABT indications, in order to assist all professionals involved in the administration of both allogeneic blood transfusions (ABT) and AABT. The present SD update pursues an identical goal. Also, as in the original SD, the SD update defines AABT as any measure aimed at reducing transfusion requirements and, therefore, the transfusion of red blood cells, preserving the patient's safety at all times. For a detailed analysis, the measures were divided into pharmacological and non-pharmacological AABT. Why did the SD 2006 consensus document need an update? There are several reasons that justify this SD update: (i) the persistent variability in the clinical use of AABT; (ii) the withdrawal of drugs for which there was a high degree of evidence in the original SD (e.g., aprotinin); (iii) new indications for drugs or devices, not covered by the original SD (e.g., prothrombin complex, fibrinogen and viscoelastic tests); (iv) warning alerts generated by government agencies regarding the adverse effects of some drugs (e.g., erythropoiesis-stimulating agents); (v) the limitations of Delphi methodology used in the first SD edition, as this methodology directly links the level of evidence to grade of recommendation, resulting in recommendations always being formulated positively, sometimes leading to confusion among the readers; and (vi) the incorporation of the Spanish Society of Hospital Pharmacy as a new, active member of the consensus. The recommendations of the updated SD are aimed at surgical, trauma or critically ill patients with blood loss who may require the use of pharmacological or non-pharmacological AABT. As in the original SD, the updated SD only contemplates the alternatives to transfusion of packed red blood cell concentrate (PRBC). For the purpose of this document, we define the transfusion rate as the number of transfused PRBC units or the percentage of transfused patients. The main question that arises in each item is formulated, positively or negatively, as: "the AABT in question reduces/does not reduce the transfusion rate". Recommendations on the use of a particular AABT to reduce transfusion 586

3 Seville Document Update 2013 rates were graded according to the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) methodology Methodology 2.1. Scientific Societies and expert panel This updated SD was produced by a panel of 40 professionals convened by six Spanish Scientific Societies involved in health care: Spanish Society of Anaesthesiology and Reanimation (SEDAR), Spanish Society of Hospital Pharmacy (SEFH), Spanish Society of Haematology and Haemotherapy (SEHH), Spanish Society of Critical Care Medicine SEMICYUC), Spanish Society of Thrombosis and Haemostasis (SETH) and Spanish Society of Blood Transfusion and Cellular Therapy (SETS). There were one general coordinator, one general vice-coordinator, nine topic coordinators (including the general coordinator), 25 collaborators, and six observers (the Presidents of the different Societies). With the exception of the members convened by SEFH, the panel composition for this updated SD did not differ substantially from that of the original SD 1. All six Societies endorsed the recommendations formulated in the SD update GRADE methodology The available evidence on the efficacy and safety of AABT was analysed according to GRADE methodology. We chose GRADE methodology because it has a number of advantages over other methodologies, such as the Delphi methodology, including: clear separation between quality of evidence and strength of recommendation; explicit, comprehensive criteria for downgrading and upgrading quality of evidence ratings; transparent process of moving from evidence to recommendations; explicit acknowledgement of values and preferences; and clear, pragmatic interpretation of strong versus weak recommendations for clinicians, patients, and policy makers, as well as for guidelines development. Strong recommendations (Grade 1) may be A, B or C depending on the quality of evidence (high, moderate, low or very low). In all cases of strong recommendation, benefits clearly outweigh risks and burden (a positive recommendation), or vice versa (a negative recommendation). However, the implications are different. A Grade 1A or 1B recommendation may be applied to most patients, in most circumstances and without reservation, whereas a grade 1C recommendation may change when evidence of higher quality become available. Weak recommendations (Grade 2) may also be A, B or C depending of the quality of evidence. Grade 2A and 2B recommendations mean that benefits are closely balanced with risks and burden and that the best action may differ depending on circumstances or patients' or societal values. In contrast, a Grade 2C recommendation means that there is uncertainty in the risk to benefit balance and that other alternatives may be equally reasonable. These differences in strength are reflected by the wording of the recommendations. Thus, when making a strong recommendation, we use the terminology, "We recommend..." or "We do not recommend...". However, when making a weak recommendation, we used a less definitive wording, such as, "We suggest..." 4. For each particular AABT, the target patient population is defined, details on implementation and doses are given, when appropriate, and a safety statement is always included 4. Finally, it should be borne in mind that for some AABT and/or patient populations no evidence-based recommendation could be given (Grade 0). 3. Non-pharmacological alternatives to allogeneic blood transfusion The non-pharmacological AABT include restrictive transfusion therapy, preoperative autologous blood donation, acute normovolaemic haemodilution, perioperative red cell salvage and assessment of haemostasis by thromboelastography Restrictive transfusion therapy in non-bleeding patients Allogeneic blood is an increasingly scarce and expensive resource; there is a lack of evidence regarding the efficacy of ABT to increase tissue oxygen consumption or reduce tissue oxygen debt in selected patients; and, more importantly, ABT is not risk-free, as there is an association between ABT and increased morbidity and mortality. All these have prompted several Scientific Societies to recommend a restrictive approach when using ABT. Thus, the level of haemoglobin (Hb) below which a PRBC unit is transfused (i.e. the "transfusion trigger") should be intimately related to the patient's ability to tolerate normovolaemic anaemia and, consequently, to his/her cardiopulmonary reserve Critically ill, trauma and/or surgical patients, without cardiac and/or central nervous system dysfunction We recommend the use of restrictive transfusion therapy, maintaining haemoglobin concentrations between 70 g/l and 90 g/l, to reduce the transfusion rate. Grade 1A. Randomised controlled trials (RCT) in euvolaemic, critically ill adults 5 and paediatric patients 6, as well as in patients undergoing vascular 7 or orthopaedic 8 surgery and in those presenting with acute upper 587

4 Leal-Noval SR et al gastrointestinal bleeding 9, have documented that the majority of such patients can tolerate haemoglobin concentrations as low as 70. Nevertheless, patients' tolerance of normovolaemic anaemia depends on their cardiopulmonary reserve, the volume and speed of blood loss, and the acute or chronic onset of anaemia Critically ill, trauma and/or surgical patients, with cardiac and/or central nervous system dysfunction We recommend the use of restrictive transfusion therapy, maintaining haemoglobin concentrations between 80 g/l and 100 g/l, to reduce the transfusion rate. Grade 1A. It has been documented that patients who present with ischaemic heart disease and/or have undergone cardiac surgery, have a poor tolerance of anaemia 10. Anaemic patients with symptomatic ischaemic heart disease and/ or brain dysfunction may require higher haemoglobin levels. In elderly anaemic patients (haematocrit <33%) with myocardial infarction, the correction of anaemia with PRBC transfusion improves the clinical outcome 11. The efficacy of PRBC is linked to the severity of anaemia and myocardial ischaemia. In anaemic patients (Hb <120 g/l) with ST elevation, PRBC transfusion improves the clinical outcome 12. Conversely, in patients with mild anaemia, as well as in those with ischaemia but without ST elevation, PRBC transfusion may worsen the clinical outcome 10. It has been shown that patients who undergo cardiac surgery and have no signs of perioperative ischaemia tolerate haemoglobin levels of 80 g/l without increased postoperative morbidity or mortality 10,13,14. A recent RCT 15 documented that in elderly patients, who had either a history of or risk factors for cardiovascular disease and had undergone surgery for hip fracture, restrictive transfusion therapy (transfusions given for symptoms of anaemia or at the physician's discretion for a Hb level <80 g/l), as compared with a liberal strategy (transfusions given below a Hb threshold of 100 g/l), did not increase rates of postoperative morbidity or mortality. Given its high metabolic rate, the brain has little tolerance of anaemia, requiring a continuous and abundant supply of oxygen. As haemoglobin-bound oxygen is the main component of oxygen transport, anaemia may adversely affect brain function in patients with traumatic brain injury, subarachnoid haemorrhage or stroke. It is likely, although not definitely documented, that anaemic patients with severe brain dysfunction may require higher haemoglobin levels than those without it 16, Safety In euvolaemic surgical patients, almost all RCT conducted to date have shown that the use of restrictive transfusion therapy does not increase the rates of postoperative morbidity or mortality or the length of hospital stay, while it does reduce both the percentage of transfused patients and the volume of allogeneic blood administered. Critically ill patients, especially those with acute brain and/or cardiac dysfunction, may have worse outcomes if they are exposed to severe anaemia. However, although anaemia may increase morbidity and mortality, PRBC transfusion does not necessarily revert the deleterious effects of anaemia Summary The majority of trauma, critically ill and/or surgical patients can tolerate haemoglobin levels of 70 g/l. However, for those presenting with acute cardiac and/or central nervous system dysfunction, a haemoglobin level of at least 80 g/l may be required. In any case, transfusion decisions should be individualised according to patient's co-morbidity, symptoms and haemoglobin concentration Preoperative autologous blood donation Preoperative autologous blood donation (PABD) is a modality of autotransfusion consisting in the withdrawal of one or several units of the patient's own blood, in the days or weeks prior to the intervention. These units undergo serological screening and storage, and may be reinfused into the patient during the procedure or in the immediate postoperative period Major orthopaedic surgery We do not recommend the routine use of preoperative autologous blood donation to reduce transfusion rates in procedures usually requiring two or fewer units of packed red blood cells per patient. Grade 1B. In adult patients undergoing major orthopaedic surgery (knee, hip or spine), data from RCT and observational studies showed a 20% reduction of the transfusion rate. However, in most of these studies transfusion criteria were not established. In addition, 60-70% of patients undergoing PABD received some type of transfusion, autologous or allogeneic, and 40% of the deposited units were not used Preoperative administration of recombinant human erythropoietin(rhuepo) 23 or perioperioperative red cells salvage (PRCS) 24 is at least as effective as PABD in reducing ABT requirements. We recommend the use of preoperative autologous blood donation to reduce transfusion rates in procedures usually requiring three or more units of packed red cells per patient, preferably with adjuvant treatment with iron and/or recombinant human erythropoietin. Grade 1C. Observational studies in patients undergoing orthopaedic procedures associated with major bleeding, such as revision of total hip arthroplasty and correction 588

5 Seville Document Update 2013 of scoliosis, have shown that PABD significantly reduces the transfusion rate, although up to 30% of PABD units were not used 25,26. In small studies of lower limb prosthetic surgery, the use of rhuepo as an adjuvant to PABD further reduced the use of ABT, although this strategy was not cost-effective 1. In addition, in patients undergoing scoliosis or complex spinal surgery, PABD with adjuvant treatment with rhuepo facilitated the donation of the requested autologous units and resulted in a significantly decreased exposure to ABT when compared with PABD alone 27,28. Furthermore, the concomitant intravenous (IV) administration of iron may enhance the bone marrow response to rhuepo, reducing the dose of the rhuepo required and, thereby, improving cost-effectiveness Elective cardiac surgery We suggest the use of preoperative autologous blood donation to reduce transfusion rates in elective cardiac surgical procedures with cardiopulmonary bypass. Grade 2B. Data from two large observational studies indicate that preoperative donation of two autologous units was the most effective strategy to prevent ABT with lower incremental costs 22,30. In some studies, adjuvant treatment with rhuepo improved the efficacy of PABD in cardiac surgery procedures, both in adults and children Oncological surgery We suggest the use of preoperative autologous blood donation to reduce transfusion rates in surgical procedures for solid cancer resection. Grade 2B. The results of various RCT and observational studies suggested that PABD may reduce ABT requirements by as much as 30% in colo-rectal cancer surgery 31, radical prostatectomy 32, and hepatic resections 33. Once again, adjuvant rhuepo treatment enhanced the efficacy of PABD in reducing ABT rates Safety The use of PABD is contraindicated permanently in seropositive patients and patients with serious cardiovascular disease, and temporarily in those with active bacterial infection, a haemoglobin level <100 g/l or body weight <10 kg 34. The results of a meta-analysis 18 indicated that the use of PABD reduced transfusion rates without increasing postoperative morbidity or mortality. However, it should be borne in mind that the incidence of adverse effects during PABD is higher than that observed for altruistic blood donation and that PABD increases the risk of receiving any type of transfusion. It is mandatory by law to discard unused units as well as seropositive units and to communicate any adverse event of PABD transfusion to the national haemovigilance system Summary The use of PABD would be indicated in patients undergoing elective surgical procedures in which the risk of transfusion is greater than 30-50% (usually with a preoperative Hb <145 g/l), patients for whom compatible ABT is difficult to find, and those who refuse to receive ABT. The risk of receiving ABT is reduced further in PABD patients receiving adjuvant rhuepo plus iron and undergoing surgical procedures that require the predeposit of three or more autologous units. Finally, it must be remembered that the PABD programme should only be implemented in those centres in which a scheduled surgery date is guaranteed Acute normovolaemic haemodilution Acute normovolaemic haemodilution (ANH) consists of the extraction and anticoagulation of a predicted volume of blood from the patient and its simultaneous exchange for a cell-free crystalloid and/or colloid solution to maintain normovolaemia. Even though extreme ANH and other types of haemodilution have been used, moderate ANH (final haematocrit 25-30%) is the preferred technique. It is used in patients undergoing major surgical procedures with moderate-to-severe blood loss, and is usually performed after the induction of anaesthesia, before the intraoperative phase of bleeding Major surgical procedures We do not recommend the routine use of acute normovolaemic haemodilution, as a single bloodsparing technique, given its low effectiveness at reducing the transfusion rate. Grade 1B. The results of two meta-analyses of 42 RCT showed that the use of ANH resulted in a small, significant reduction in transfusion rate 18,36. However, the effectiveness of ANH was virtually eliminated in studies in which a transfusion protocol was applied and when partnered or compared with other AABT (e.g., PABD, tranexamic acid) 18,36, Safety This AABT should only be used in those institutions that can implement logistics for blood removal and volume replacement without detracting from patient care, and following the recommendations of published guidelines 38. Bags of blood can be kept in the operating theatre at room temperature for a maximum of 6 hours and reinfused in reverse order of their removal. Although in two meta-analyses ANH was not associated with increased risks of morbidity and mortality, the quality of the evidence in this regard is moderate to low 36,37. In adult patients undergoing cardiac surgery, ANH has been associated with increased rates of kidney failure 39 and disorders of psychomotor development in children 40. In 589

6 Leal-Noval SR et al contrast, the use of ANH was associated with reduced rates of postoperative infection in people undergoing orthopaedic surgery Summary Most of the studies did not show a significant reduction of transfusion rate, although ANH has contributed to the concept of tolerance to low haemoglobin levels in low-risk patients. Therefore, despite its low cost, ANH should only be used in association with other AABT in selected patients, except in those centres in which no other AABT can be implemented. The available evidence on other modalities of haemodilution, such as moderate hypervolaemic haemodilution or augmented acute haemodilution, is insufficient to be able to make any recommendation Perioperative red cell salvage Perioperative red cell salvage (PRCS) is defined as the collection of the patient's blood in surgical procedures in which blood loss is significant. During surgery, intraoperative cell salvage is performed using devices that aspirate, anticoagulate, wash and concentrate the blood shed from the surgical field, which is returned to patients as PRBC in saline. After surgery, postoperative cell salvage consists of the collection and reinfusion of blood lost through the wound drains. When intraoperative cell salvage is not indicated, postoperative cell salvage is usually performed using devices that collect and return unwashed filtered shed blood Major orthopaedic surgery a) Total knee or hip arthroplasty We recommend the use of perioperative red cell salvage, reinfusing filtered and/or washed salvaged blood, to reduce the transfusion rate. Grade 1B. In patients undergoing surgery for primary total knee arthroplasty 42,43 or total hip arthroplasty 44,45, postoperative recovery and reinfusion of washed or filtered shed blood reduced the absolute risk of receiving ABT by 20% (11% versus 30%), but not the number of ABT units per transfused patient. Postoperative cell salvage with washed blood was also effective in reducing the transfusion rate in revisions of total hip arthroplasties, especially if it was associated with other AABT 46. b) Spine surgery We recommend the use of perioperative red cell salvage, within a multimodal blood management programme, for reducing the transfusion rate in patients undergoing surgery for scoliosis or complex degenerative spine pathology. Grade 1C. In instrumental lumbar or lumbo-sacral spine surgery, with or without iliac crest bone autografting, postoperative cell salvage significantly reduced the volume of ABT, but not the percentage of patients who underwent ABT 47. In surgery for correction of scoliosis, in which up to 90% of the patient's estimated blood volume can be lost, PRCS alone or associated with other AABT, significantly reduces transfusion rate 48, Cardiac surgery We recommend the use of perioperative red cell salvage to reduce transfusion rates in elective cardiac surgical procedures with cardiopulmonary bypass. Grade 1B. In cardiac surgery with cardiopulmonary bypass (CPB), salvage, washing and reinfusion of blood from the surgical field, the cardiotomy reservoir and the postoperative chest drainage reduced the percentage of patients exposed to ABT when compared to a control group, but not the number of ABT units infused per patient 50. However, PRCS was not effective if it was limited to processing pericardial suction 51 or used in cardiac surgery without CPB Major vascular surgery We recommend the use of perioperative red cell salvage to reduce transfusion rates in vascular surgical procedures for abdominal aorta aneurysm repair. Grade 1B. Several studies on elective surgery for repair of an abdominal aorta aneurysm showed that intraoperative cell salvage reduced, by 40%, the absolute risk of exposure to ABT and the ABT volume when compared to control management 53. It has been estimated that intraoperative cell salvage is cost effective when blood loss exceeds 800 ml. In surgery to repair a ruptured abdominal aorta aneurysm, intraoperative cell salvage reduced ABT requirements by three units per patient 53,54. In elective and ruptured abdominal aorta aneurysm, the use of an endovascular prosthesis reduced bleeding and transfusion requirements in comparison with open surgery, although the role of intraoperative cell salvage in this setting has not been sufficiently studied Other surgical procedures We suggest the use of perioperative red cell salvage, with washing and filtering and/or irradiation of salvaged blood, for reducing transfusion rates in surgical resection of hepatic or urological cancers, Caesarean section or ruptured ectopic pregnancy. Grade 2C. Several RCT and observational studies suggest that PRCS may reduce transfusion rates in patients undergoing liver transplantation for hepatocellular 590

7 Seville Document Update 2013 carcinoma or cirrhosis 55, radical prostatectomy 56, Caesarean section 57, rupture of ectopic pregnancy 58, or abdominal trauma Safety Data from clinical studies conducted in different types of urgent or elective surgery clearly showed that PRCS did not increase either the risk of postoperative morbidity or mortality or the length of hospital stay. However, some serious adverse effects have been reported, especially coagulopathy, when large volumes of recovered and processed blood are transfused. As for orthopaedic surgery, although serious adverse effects have been barely detected, more than 1,000 ml of unwashed filtered blood should not be reinfused 60. In contrast, the results of a systematic review indicate that reinfusion of salvaged unwashed filtered blood after cardiac procedures is not recommended 18. The indication for PRCS in cancer surgery and Caesarean section is controversial. In cancer surgery, the results of a recent meta-analysis showed that PRCS did not increase the incidence of metastasis or cancer recurrence Summary Intraoperative cell salvage would be indicated in patients undergoing elective surgery in which a blood loss of more than 1,500 ml is expected and at least the equivalent of units of PRBC can be recovered. On the other hand, the use of postoperative salvage and reinfusion of unwashed filtered blood would be restricted to patients with haemoglobin <14 g/dl undergoing elective prosthetic surgery in which a postoperative blood loss volume between 500 ml and 1,000 ml is expected, and at least the equivalent of 1 unit of PRBC can be recovered 1. It must be stressed that the recommendations given in this section are limited by the poor methodological quality of many of the studies analysed, which generally involved a small number of patients (less than 60 per arm). In addition, as the trials were not blinded and lacked adequate concealment of treatment allocation, transfusion practices may have been influenced by knowledge of the patient's treatment status, thus biasing the results in favour of PRCS. Finally, it is worthy noting that the contribution of PRCS to ABT reduction decreased when a transfusion protocol was implemented. at the bedside). Thus, TEG has significant advantages compared to conventional coagulation tests; namely, rapid results to guide haemostatic therapy, leading to early clinical decisions, and overall evaluation of coagulation in whole blood 62,63. Up to 35% of the bleeding trauma patients present with abnormal coagulation tests upon hospital admission. The so-called "acute traumatic coagulopathy" 64 is an independent predictor of poor outcome and, if present, needs to be treated early and aggressively. On the other hand, surgical patients may also develop different coagulation disorders, which should be managed on an individual basis. TEG enables individualised administration of blood components (plasma and platelet concentrates) and clotting factor concentrates (fibrinogen and prothrombin complex) Bleeding in patients with severe trauma We recommend the use of thromboelastography to guide the replacement of blood clotting factors and reduce the transfusion rate. Grade 1C. Patients with bleeding injuries may develop early clotting alterations (within 30 minutes following trauma), including hypocoagulability, hypercoagulability or hyperfibrinolysis 62,63. At least 20 studies have documented that the use of TEG enables more efficient management of coagulation and may reduce transfusion rate 62, Bleeding in surgical patients We recommend the use of thromboelastrography to guide the replacement of blood clotting factors and reduce the transfusion rate. Grade 1C. A retrospective study that included more than 3,000 patients undergoing cardiovascular surgery documented that TEG significantly decreased the rates of transfusion and thromboembolic events 65. Retrospective studies involving small numbers of patients undergoing vascular, liver or obstetric surgery concluded that TEG reduced transfusion rates and enabled early treatment of coagulation disorders 66, Safety The use of TEG carries no risks for the patient. However, as TEG does not evaluate platelet function, patients with platelet dysfunction should be assessed with other technologies Point-of-care coagulation testing: thromboelastography Thromboelastrography (TEG) provides a global evaluation of the viscoelastic properties of a clot (cellular model of blood coagulation), displays the results graphically and enables the analysis of clot formation and lyses in less than 10 minutes at the point-of-care (e.g Summary TEG is a useful technique for the early assessment of coagulation disorders and facilitates selective administration of blood components and clotting factors. Although its use is associated with a significant decrease in ABT, it does not diminish the high mortality rate of patients with severe bleeding

8 Leal-Noval SR et al 4. Pharmacological alternatives to allogeneic blood transfusion Pharmacological AABT include measures to decrease bleeding, stimulate erythropoiesis and improve oxygen transport. Pharmacological alternatives to decrease bleeding The reduction of perioperative blood loss is essential to decrease a patient's exposure to ABT. This reduction may be achieved through proper management of platelet anti-aggregant and anticoagulation therapy, maintenance of normothermia, use of controlled, induced or permissive hypotension, meticulous surgical haemostasis and, when possible, minimally invasive surgical techniques and the use of low-vacuum drains. Finally, the administration of drugs that promote clot formation, ensure clot stability and/or delay clot lysis should be evaluated Prothrombin complex concentrates Prothrombin complex concentrates (PCC) are plasma derivatives that contain varying amounts of clotting factors II, IX and X ("three-factor PCC", marketed in the USA) or clotting factors II, VII, IX and X ("four-factor PCC", marketed in Europe). The three "four-factor PCC" sold in Spain have similar efficacy, but they differ slightly in composition. To prevent thrombin formation, PCC contain protein C, protein S, antithrombin III and/or heparin Patients being treated with vitamin K antagonists and presenting with active bleeding or requiring urgent or emergent surgery We suggest the administration of prothrombin complex concentrate to reduce bleeding and/or transfusion rate. Grade 2A. Within 10 to 30 minutes after administration of a PCC, virtually all patients achieve normalisation of their International Normalised Ratio (INR) values When PCC administration was aimed to prevent bleeding in patients who were to undergo surgery or invasive procedures or to decrease bleeding in patients with active haemorrhage, most of the studies documented its efficacy in achieving these goals 72. Clinical guidelines suggest the use of four-factor PCC in bleeding patients treated with vitamin K antagonists (VKA), regardless of INR value 73. In surgical patients, PCC may be preferable to rfviia and/or fresh-frozen plasma (FFP) 74. However, the small number of studies, the retrospective nature of most of them, the low numbers of patients included, the concomitant treatment with FFP or other pro-haemostatic drugs, the absence of control groups, and methodological differences do not allow solid conclusions to be drawn Patients being treated with vitamin K antagonists and presenting with intracranial haemorrhage We recommend the administration of prothrombin complex concentrate to reduce bleeding. Grade 1C. Intracranial haemorrhage is the most serious event associated with anticoagulation with VKA. The risk of intracranial haemorrhage doubles for every point increase in INR. The rates of haematoma expansion, neurological sequelae and mortality are higher in VKA-associated intracranial haemorrhage than in intracranial haemorrhage of other aetiologies The mortality rate within the first 24 hours can reach 33% 79,80. The INR is corrected and bleeding controlled more effectively in patients treated with PCC than in those treated with FFP 81,82. However, the rates of mortality and sequelae remain consistently high, regardless of the treatment chosen 79, Patients not being treated with vitamin K antagonists and presenting with coagulopathy in the setting of trauma, perioperative haemorrhage or acute liver failure We suggest the administration of prothrombin complex concentrate to reduce bleeding and/or transfusion rate. Grade 2C. Bleeding in trauma patients. Generally patients with massive haemorrhage receive more PRBC units than FFP units (ratio 3:1 or higher). Although controversial, data from trauma patients with critical bleeding in the military context have documented that mortality improved when patients received similar amounts of PRBC, FFP and platelet concentrates (i.e. a 1:1:1 ratio), thus suggesting the need to provide large amounts of clotting factors from the onset of bleeding 83,84. As a PCC quickly delivers large amounts of clotting factors, early PCC administration may reduce transfusion requirements 85. Bleeding in surgical patients. PCC administration is associated with decreased transfusion requirements in the perioperative period 86, especially in patients undergoing cardiac surgery 65. Acute liver failure. One observational study suggests that PCC could be useful in the prophylaxis or treatment of bleeding in patients with deficiency of liver-dependent clotting factors secondary to acute liver failure Patients being treated with vitamin K antagonists and requiring immediate reversal of anticoagulation: prothrombin complex concentrate versus fresh-frozen plasma or recombinant activated factor VII We suggest that prothrombin complex concentrate is superior to fresh-frozen plasma or recombinant activated factor VII for reducing bleeding and/or transfusion rate. Grade 2C. 592

9 Seville Document Update 2013 FFP contains varying amounts of all coagulation factors. Although the optimal FFP dose has not been established, a dose of 15 ml/kg is usually recommended. However, doses as high as 30 ml/kg may be needed to provide optimal amounts of clotting factors 88,89. Compared with FFP, PCC has several advantages: (i) greater content of liver-dependent clotting factors, but lacks fibrinogen and factor XIII; (ii) no need for group matching (whereas this is necessary for FFP); (iii) faster administration (FFP must be thawed, delaying its administration); (iv) it corrects the INR more quickly and effectively does than FFP (less than 30 minutes with PCC); and (v) smaller volumes necessary (at the suggested dose, at least 1,000 ml of FFP are needed for a 70 kg patient, which may lead to transfusion-associated cardiovascular overload [TACO] and transfusion-related acute lung injury [TRALI]) Most guidelines 73,74 and observational studies 81,82 suggest that PCC is superior to FFP in controlling VKA-induced haemorrhagic events. In mice with VKA-induced intracranial haemorrhage, PCC or FFP was more effective than rfviia at halting expansion of the haematoma 90. Although the administration of rfviia reduced the size of the haematoma in patients with intracranial haemorrhage, mortality remained invariably high. In addition, the high rate of thromboembolic events has discouraged the routine use of rfviia in VKA-treated patients with critical haemorrhage Dosage In patients with intracranial haemorrhage, the administration of IU/kg of PCC slows the expansion of the haematoma, corrects the INR in less than 30 minutes and enables surgical control of the haematoma 80. In general, either fixed or individualised doses can be used. A recent study found no advantage from using individualised doses, recommending a single fixed dose of 1,000 IU PCC for all situations 92. However, most authors recommend individualised doses (based on the patient's weight and current and target INR), which vary between IU/kg. In all cases, administration of PCC should be supplemented with 5-10 mg of vitamin K, IV. Generally, the PCC dosage is based on the percentage of plasma clotting factors, so the INR must be converted to this percentage (Table I). The dose is then calculated using the equation: units of factors of PCCP = (target level of factors [%] current level of factors [%]) body weight [kg]. For example, for a man weighing 80 kg with a current INR of 7.5 (5% of plasma clotting factors) and a target INR of 1.5 (40% of plasma clotting factors), the PCC dose would be (40 5) 80=2,800 IU 93. Table I - Conversion of INR values to % of plasma clotting factors. INR % plasma clotting factors Supra-therapeutic range > Therapeutic range Infra-therapeutic range Safety Variable, but low rates of thrombo-embolic events, especially in arterial territories (stroke, myocardial infarction, pulmonary embolism) have been reported in patients treated with PCC 65,70,94. However, in the majority of cases, a cause-effect relationship between PCC administration and increased rates of clinically relevant thromboembolic phenomena has not been documented. Most Authors consider PCC as a safe drug Summary As in other recent clinical practice guidelines, we suggest the administration of PCC for patients being treated with VKA who present with bleeding or require invasive procedures, although this is a weak recommendation based on data from retrospective studies involving few patients (Grade 2C). However, a strong recommendation is to administer PCC to VKA-treated patients with intracranial haemorrahge (Grade 1C), since several retrospective studies and at least two prospective studies have documented that administration of PCC in this context resulted in a decreased rate of haematoma expansion. Finally, PCC could potentially be useful in bleeding patients not being treated with VKA (Grade 2C) Fibrinogen Adequate levels of fibrinogen ( g/l) are critical to achieve effective haemostasis. Fibrinogen facilitates platelet aggregation and, when activated by thrombin, gives rise to fibrin polymers, which are the basis of clot formation 66. Severe haemorrhage involves the loss of coagulation factors, including fibrinogen. Intensive resuscitation with crystalloid solutions further dilutes existing clotting factors. In addition, colloids may interfere with the formation of an effective clot, by altering its firmness and stability. Both mechanisms (loss and dilution of clotting factors) lead to coagulopathy. The presence of coagulopathy is an independent risk factor for poor clinical outcome In addition, pre-operative fibrinogen levels are predictive of perioperative bleeding 66,95,

10 Leal-Noval SR et al Fibrinogen seems to be the coagulation factor that first reaches a critically low level (<1 g/l) drung active bleeding. There are three ways to replace fibrinogen: FFP, cryoprecipitate and fibrinogen concentrate. The compound most commonly used in Spain is fibrinogen concentrate, which is also a plasma derivative, but unlike FFP and cryoprecipitate, does not require cross-matching and is administered quickly (up to 6 g can be given in less than 3 minutes) 97, Patients with traumatic bleeding We recommend the administration of fibrinogen concentrates to reduce bleeding and/or transfusion rate. Grade 1C. European guidelines on traumatic bleeding recommend the administration of fibrinogen in all cases of severe bleeding, in which TEG shows a fibrinogen deficiency or plasma fibrinogen is below 2 g/l 99. Recent reviews of retrospective studies of patients with bleeding trauma conclude that TEGguided fibrinogen administration, with or without PCC, reduces the transfusion rate and may improve clinical outcome 62-67,95,96,100, Bleeding in surgical patients We suggest the administration of fibrinogen concentrates to reduce bleeding and/or transfusion rate. Grade 2B. In patients undergoing surgery to repair a ruptured abdominal aortic aneurysm, administration of massive amounts of FFP significantly reduced mortality rate from 39% to 15%, suggesting that early administration of clotting factors may improve the clinical outcome 102. In addition, preoperative and postoperative infusion of high doses of fibrinogen (6 g in 2 minutes) increased clot firmness and reduced bleeding and transfusion requirements 102. In a retrospective study of more than 3,000 patients undergoing cardiac surgery, TEG-guided administration of fibrinogen and PCC reduced the rates of transfusion and thromboembolic events 65. A recent RCT documented that haemostasis is more effectively restored with fibrinogen and FFP than with FFP alone 103. One RCT involving 20 patients undergoing radical cystectomy documented a significantly lower transfusion rate in the group treated with fibrinogen 104. A series of six cases shown that combined administration of fibrinogen and other blood products may control bleeding in patients with obstetric haemorrhage Dosage Fresh-frozen plasma contains approximately 2 g/l of fibrinogen; therefore, large volumes of FFP (2 L) are required to increase fibrinogen levels by 1 g/l. The concentration of fibrinogen is higher in cryoprecipitate than in FFP 66,95. There is no agreement on a standard fibrinogen dose. Prophylactic doses of 2 g are given before surgery and doses of 6 g have been given in ongoing severe bleeding 97,101, although the most usual dosage is 2-4 g. The fibrinogen dose can be calculated using the following formula 66 : doses of fibrinogen = target fibrinogen increment (g/l) plasma volume (L). The plasma volume can be estimated to be 0.04 L/Kg. As an example, 5.6 g of fibrinogen are required to raise the plasma fibrinogen concentration from 1 g/l to 3 g/l in a 70 kg bleeding patient ( = 5.6) Safety Fibrinogen is considered a safe drug 96. However, its use has been associated with increased risks of coronary ischemia 66 and arterial and venous thromboembolic events when high doses are administered (up to 12 g) 106. Despite being a plasma derivative, transmission of blood-borne infections have not been described with fibrinogen Summary The level of fibrinogen is critical to achieve effective haemostasis, since it is the coagulation factor that first reaches a critically low level (<1 g/l) during severe bleeding. Observational studies and case series suggest that early administration of fibrinogen can be effective in reducing the transfusion rate. Fibrinogen is often administered together with FFP and PCC, which prevents a proper assessment of its effectiveness. Administration of fibrinogen should ideally be guided by bed-side TEG rather than by conventional laboratory tests 107. However, large RCT are needed before recommending its generalised use for the treatment of acquired fibrinogen deficiency in critical bleeding Synthetic antifibrinolytic agents Within this pharmacological group, we will discuss the efficacy and safety of tranexamic acid (TXA) and epsilon-aminocaproic acid (EACA). We will not consider the use of aprotinin, as it has been withdrawn from the market. TXA and EACA are synthetic lysine analogues that competitively inhibit the binding of plasminogen to lysine residues on the fibrin surface, thus preventing its conversion into active plasmin. TXA is 10 times more potent than EACA Major orthopaedic surgery We suggest the administration of tranexamic acid to reduce perioperative blood loss and/or transfusion rate. Grade 2A. 594

11 Seville Document Update 2013 In several studies, with explicit transfusion protocols, in patients undergoing total hip arthroplasty 109 or total knee arthroplasty 110, IV administration of TXA reduced the volume of perioperative blood loss and the requirements for ABT by as much as 25%. Topical TXA, as irrigation or intra-joint injection, also reduced postoperative bleeding, but its effect on transfusion rate was less evident 111. In spine surgery, primarily scoliosis, TXA administration, in combination with other AABT, resulted in a dose-dependent reduction of bleeding volume and ABT volume, but generally did not affect the percentage of patients who received ABT We do not recommend the administration of ɛ-aminocaproic acid for reducing perioperative blood loss and/or transfusion rate. Grade 1B. Results of a meta-analysis did not show that EACA has a beneficial effect on reducing the transfusion rate in patients undergoing orthopaedic surgery (RR: 0.73; 95% CI ) Cardiac surgery We recommend the administration of tranexamic acid to reduce perioperative blood loss and/or transfusion rate. Grade 1A. Compared with placebo, TXA reduced transfusion rate and the risk of reoperation for persistent or recurrent bleeding in patients undergoing cardiac surgery with CPB 116. In myocardial revascularisation surgery without CPB, TXA administration reduced the risk of receiving ABT 117. Topical administration of TXA reduced postoperative bleeding, but not ABT requirements 118. We recommend the administration of ɛ-aminocaproic acid for reducing perioperative blood loss and/or transfusion rate. Grade 1B. In cardiac surgery with CPB, EACA administration reduced ABT requirements and the rate of re-exploration for bleeding 116. On the other hand, in the BART study, EACA and TXA showed similar efficacy in reducing bleeding and ABT requirements 119, and the blood-saving effects of both agents were observed even in patients treated with aspirin Miscellaneous surgery We suggest the administration of tranexamic acid to reduce perioperative blood loss and/or transfusion rate in patients undergoing gynaecological or urological surgery. Grade 2A. In elective Caesarean section, one RCT including 660 patients showed that TXA administration reduced the volume of blood loss, the percentage of women with a blood loss of more than 1,000 ml and the need for uterotonics 123. In radical retropubic prostatectomy, one RCT involving 200 patients showed that administration of TXA reduced intraoperative blood loss and transfusion rate Trauma patients with severe bleeding We recommend the administration of tranexamic acid to reduce blood loss and/or mortality rate. Grade 1B. The results from the CRASH-2 study, a RCT involving more than 20,000 patients from 274 hospitals in 40 countries, showed that administration of TXA within 8 hours of injury significantly reduced mortality from all causes (14.5% vs 16%), including mortality due to bleeding (4.9% vs 5.7%) 125. More recently, a retrospective study of 896 military patients wounded in combat showed an association between the administration of TXA and lower rates of coagulopathy and mortality, especially among those who needed massive transfusion Gastrointestinal haemorrhage We suggest the administration of tranexamic acid to reduce blood loss and improving clinical outcome. Grade 2A. In a meta-analysis of RCTs, including 1,267 patients with gastrointestinal haemorrhage due to ulcer or mucosal erosion, the administration of TXA reduced by 20-30% the rate of re-bleeding, avoided surgery in 40% of patients, and decreased mortality rate by 40%. Despite these good results, TXA is not frequently used in gastrointestinal haemorrhage, mostly because of the efficacy of other compounds and the use of endoscopic procedures to arrest bleeding Hepatic surgery We recommend the administration of tranexamic acid to reduce perioperative blood loss and/or transfusion rate. Grade 1B. In liver transplantation, the administration of high doses of TXA reduced ABT requirements, while the continuous infusion of low doses of TXA reduced fibrinolysis but not ABT requirements 121. A RCT of 214 patients undergoing liver resection showed that TXA administration reduced intraoperative bleeding and surgery time and abolished the need for ABT Dosage The doses of TXA used most frequently in the studies reviewed were: - Total hip or knee arthroplasty: an initial dose of mg/kg before surgery, followed or not by infusion of 1 mg/kg/h for 4-6 h or the repetition of the initial dose in the postoperative period. - Spinal surgery: an initial dose of mg/kg, followed by an infusion of 10 mg/kg/h for 4-6 h. - Cardiac surgery with CPB and liver transplantation: an initial dose of 30 mg/kg followed by an infusion 595